Achieving effective oral delivery of therapeutic proteins means circumventing physiological barriers which seem to have evolved specifically to prevent this process. There are two classes of barriers, the intestinal wall and enzymatic degradation. Permeation constraints at the intestinal wall are attributed to the large molecular size of the proteins which prevent the paracellular route of permeation while their high aqueous solubility/hydrophilicity greatly constrains transcellular diffusion. The GI tract, on the other hand, contains a variety of proteases designed to degrade large proteins all the way to di-and tri-peptides by the time they reach the basolateral side of the epithelial cell layer of the small intestine.

Many approaches have been and are being investigated to address the challenge of oral protein delivery, only a subset of which falls in the category of nanotechnology. This article treats a number of these nanotechnologies including micro-machined devices delivering nanoliter volumes, mesoporous silica nanoparticles, protein nano-vessels and receptor-mediated endocytotic delivery of protein nanoparticles.